Targeting Angiogenesis

An unmet need in gastric cancer

Gastric cancer is the fifth most common cancer in the world and the third-leading cause of cancer-related deaths. Asia in particular has the highest incidence rates and remains a significant public health problem as it often presents itself at the advanced stages with poor prognosis. The focus of research on new therapeutic strategies has moved from standard chemotherapy agents to designing agents that would target specific receptors and pathways. Encouraging developments and results from significant clinical trials have injected new hope of increased survival for patients. How does this impact the way advanced gastric cancer is treated?

Targeted therapy for disrupting tumour blood circulation - anti-angiogenesis – has finally found its place under the sun in advanced gastric cancer.

Despite the declining incidence of gastric cancer worldwide, statistics from the International Agency for Research on Cancer (GLOBOCAN 2012) showed that, nevertheless, close to a million new cases are diagnosed annually worldwide making gastric cancer the fifth biggest cancer scourge on the globe. Coupled with a mortality rate in excess of 65 per cent, gastric cancer stands today as the third most common cause of cancer death around the world. East Asia and Southeast Asia, in particular, carry more than their fair share of this disease burden given the relatively higher incidence of gastric cancer in these regions compared with the rest of the world.

Precious little progress has been made over the last decade in the field of chemotherapy for stage IV gastric cancer (stage IV being the commonest stage at diagnosis worldwide) beyond the use of a platinum analog and fluoropyrimidine cytotoxic doublet as first line treatment.

While survival has reached crescendo after crescendo in other major cancer types such as breast cancer, colorectal cancer and lung cancer with beaucoup success stories in research, gastric cancer has been very much of a laggard.

The results of the ToGA trial in 2010 demonstrating the benefit of the addition of a monoclonal antibody–tastuzumab-in the subgroup of advanced gastric cancers with amplification of the Human Epidermal growth Receptor 2 (HER2) represented the first major breakthrough beyond platinum and fluoropyrimidine. This HER2 over-expressing subgroup, however, forms only about a quarter of all advanced gastric cancer encountered in the clinical setting. Hence, this strategy was not widely applicable.

Breakthrough in Anti-Angiogenesis Strategy

2014 brought more good news by way of the REGARD and RAINBOW trials firmly establishing the role of ramucirumab (Cyramza®) and the importance of anti-angiogenesis in the treatment of advanced gastric cancer beyond first line.

The formation of a new blood microcirculation, known as angiogenesis, has long been recognised as one of the hallmarks of cancer survival, proliferation and dissemination. Novel treatment targeting tumour angiogenesis with a monoclonal antibody – bevacizumab - had considerable success in multiple tumour types, notably colorectal cancer, lung cancer, ovarian cancer and brain cancer (glioblastoma multiforme).

Disappointingly, the first foray into anti-angiogenesis in gastric cancer using the same antibody hit a brick wall. The large-scale AVAGAST trial failed to demonstrate any significant prolongation of survival with the addition of bevacizumab to first line chemotherapy in gastric cancer. A tweak of the anti-angiogenic strategy using ramucirumab finally achieved the long awaited breakthrough.

The underlying mechanism for tumour blood vessel formation involves, inter alia, the interaction between the growth-signal-generating receptor on blood vessels, the vascular endothelial growth factor receptor (VEGFR), and the activating ligand, known as vascular endothelial growth factor (VEGF). While bevacizumab works by binding to the latter (VEGF), ramucirumab blocks the former (VEGFR).

New Standard of Care in Second Line Treatment

The current regulatory approval for use of ramucirumab in Asian jurisdictions (Japan, South Korea, Taiwan, Hong Kong and Singapore) stands on the back of two phase III randomised trials comparing ramucirumab against placebo (REGARD trial) or ramucirumab in combination with chemotherapy against chemotherapy alone (RAINBOW trial), following the failure of standard first-line treatment.

The REGARD trial proved that the use of ramucirumab reduced the odds of death by 22 per cent over placebo. The RAINBOW trial demonstrated a further reduction in the odds of death by 20 per cent with the addition of ramucirumab over and above the benefit accorded by second-line chemotherapy alone.

Better therapeutic options in the setting of second line treatment of advanced gastric cancer is of great interest in the medical oncology community as chemotherapy alone is of very limited efficacy in this situation with generally poor treatment outcomes.

The two trials further gave assurance of the safety profile of ramucirumab. The adverse effects encountered by trial patients were graded, as commonly practiced in well-conducted clinical trials, into 4 categories according to severity. Side effects related to the mechanism of action of treatment targeting tumour angiogenesis includes abnormal bleeding, thrombosis of either the arterial or venous circulation and high blood pressure. Serious side effects (grades 3 or 4) in each of these categories were below 10 per cent when ramucirumab is used on its own. Serious bleeding, a side effect of particular concern, occurred in only 3 per cent of cases.

For patients with advanced gastric cancer, gauged by their treating oncologists to be well enough to tolerate further treatment with chemotherapy following the failure of standard first-line treatment, the combination of ramucirumab with chemotherapy as second-line treatment should now be considered the new standard of care.

Developments to Watch in Gastric Cancer Research

Ramucirumab has also received approval for use in second line treatment of advanced colorectal cancer and advanced non-small cell lung cancer in Singapore.

Going forward, oncologists await with bated breath the results of the phase III clinical trial – RAINFALL - exploring the role of ramucirumab as first-line treatment in combination with platinum analog and fluoropyrimidine chemotherapy in treatment-naïve patients with advanced gastric cancer.

Lastly, another space to watch in gastric cancer research is the role of immuno-oncology in the treatment of advanced gastric cancer. Antibodies directed against the immune checkpoint PD-1, may yet find a new role in gastric cancer. Riding on the tail wind of the encouraging results from the early-phase KEYNOTE 012 trial using pembrolizumab - an anti-PD1 monoclonal antibody - a phase III trial, KEYNOTE 061, exploring its merits vis-à-vis chemotherapy in the second-line setting is rapidly accruing.

After a long hiatus, the recent success marked by the newly established role of anti-angiogenesis in the treatment of advanced gastric cancer, will hopefully herald a new dawn of treatment breakthroughs in research, in the days to come.

Author Bio

Wong Seng Weng is currently the medical director and consultant medical oncologist of The Cancer Centre, and a visiting consultant of Mount Elizabeth Hospital, Mount Elizabeth Novena Hospital and Gleneagles Hospital in Singapore. His sub-specialties include breast cancer, lung cancer and gastrointestinal cancers. Dr Wong obtained his basic medical degree from the National University of Singapore (NUS) under the Lim Boon Keng and Tan Siak Kew Scholarships. He completed his post-graduate training in Internal Medicine and obtained his membership of the Royal College of Physicians of the United Kingdom (MRCP UK). In the area of research, he holds the appointment of adjunct clinician scientist of the Institute of Bioengineering and Nanotechnology (IBN) in the Agency for Science, Technology and Research (A*STAR).